G{alpha}i2 Signaling Regulates Inflammasome Priming and Cytokine Production by Biasing Macrophage Phenotype Determination [INNATE IMMUNITY AND INFLAMMATION]

Macrophages exist as innate immune subsets that exhibit phenotypic heterogeneity and functional plasticity. Their phenotypes are dictated by inputs from the tissue microenvironment. G-protein–coupled receptors are essential in transducing signals from the microenvironment, and heterotrimeric Gα signaling links these receptors to downstream effectors. Several Gα_i-coupled G-protein–coupled receptors have been implicated in macrophage polarization. In this study, we use genetically modified mice to investigate the role of Gα_i2 on inflammasome activity and macrophage polarization. We report that Gα_i2 in murine bone marrow–derived macrophages (BMDMs) regulates IL-1β release after activation of the NLRP3, AIM2, and NLRC4 inflammasomes. We show this regulation stems from the biased polarity of Gα_i2 deficient (Gnai2^–/–) and RGS-insensitive Gα_i2 (Gnai2^G184S/G184S) BMDMs. We determined that although Gnai2^G184S/G184S BMDMs (excess Gα_i2 signaling) have a tendency toward classically activated proinflammatory (M1) phenotype, Gnai2^–/– BMDMs (Gα_i2 deficient) are biased toward alternatively activated anti-inflammatory (M2) phenotype. Finally, we find that Gα_i2-deficient macrophages have increased Akt activation and IFN-β production but defects in ERK1/2 and STAT3 activation after LPS stimulation. Gα_i2-deficient macrophages also exhibit increased STAT6 activation after IL-4 stimulation. In summary, our data indicates that excess Gα_i2 signaling promotes an M1 macrophage phenotype, whereas Gα_i2 signaling deficiency promotes an M2 phenotype. Understanding Gα_i2-mediated effects on macrophage polarization may bring to light insights regarding disease pathogenesis and the reprogramming of macrophages for the development of novel therapeutics.

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